Fibulin-2 is a key mediator of the pro-neurogenic effect of TGF-beta1 on adult neural stem cells?

MARIA CELESTE LEAL; PABLO DANIEL RADICE; PATRICIA MATHIEU; MARIA ISABEL FARIAS; CARINA CINTIA FERRARI; MARIANA PUNTEL; MARIANO SALIBE; ARIEL CHERNOMORETZ; FERNANDO JUAN PITOSSI

Rio de Janeiro

Congreso; IBRO 2015 9th World Congress; 2015

IBRO

The adult brain possesses neurogenic regions that contain adult neural stem cells (NSC), which are able to proliferate and generate new neurons, astrocytes and oligodendrocytes. The molecular mechanisms of this differentiation process arent yet completely known. Our lab demonstrated that immune system cytokines participate in the neurogenic niche, regulating the neuronal differentiation. In particular, we demonstrated that TGFbeta1 induces neurogenesis in vivo and increases the ratio of neuronal progenitors (βIIITubulin+ cells) obtained from NSC in vitro. The aim of this project was to identify molecules participating in the pro-neurogenic process induced by in vitro. Through a functional genomics assay, we detected 10 genes with differential expression induced by TGFBbeta1, and validated them by qPCR. We selected Fibulin 2 (Fbln2, which exhibited the highest induction rate) as a candidate for a functional validation of its potential role in the neurogenic process. We silenced Fbln2 expression with specific siRNA during the neural differentiation process induced by TGFbeta1 in NSC primary cultures. The specific Fbln2 siRNA, but not the scramble, blocked the pro-neurogenic effect of TGFbeta1. Notably, Fbln2 induction was observed specifically in βIIITubulin- but not in GFAP+ cells, suggesting an indirect effect over the neuronal progenitor population. Moreover, TGFbeta1 injections in the subventricular zone in adult rats showed a robust expression of Fibulin-2 but not in the contralateral side. Fibulin-2 induction co-localize to GFAP-expressing cells, similarly as in the in vitro model. These results indicate Fbln2 as a candidate molecule to mediate TGFbeta1 neurogenic effect, attributing for the first time a role in neurogenesis to this molecule.